chrX-71110964-C-T

Variant names:

• chrX-71110964-C-T
• rs1057520644
• NM_000206.3:c.202G>A

Variant summary

Our verdict is Pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2_Supporting PP4_Moderate PS4

This summary comes from the ClinGen Evidence Repository: NM_000206.3(IL2RG):c.202G>A is a missense variant predicted to cause substitution of Glutamic Acid by Lysine at amino acid 68 (p.Glu68Lys). The variant is absent in gnomAD v4 (PM2_supporting). Male patient (0.5 pt.) with SCID (0.5 pt.), genome sequencing conducted (1 pt.), Absent CD132 expression (1 pt.), T-B+NK- lymphocyte subset profile (0.5 pt.); total :3.5 pts PMID:30778343 (PP4_moderate). This variant is found in multiple unrelated affected probands (total pts. >16) (PS4_very strong) (PMIDs: 9058718, 24534054,11129345, 32477911,31456805, 27484032,31031743,30778343).As per the SCID VCEP specifications and the Bayesian interpretation of the ACMG/AMP combining rules, 1 Very Strong,1 Moderate and 1 Supporting criteria results in a Pathogenic classification. In summary, this variant meets the criteria to be classified as Pathogenic for X-linked severe combined immunodeficiency due to IL2RG deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_supporting,PP4_moderate,PS4_very strong (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16608976/MONDO:0010315/129

• Frequency: Genomes: not found (cov: 21)
• Consequence: IL2RG NM_000206.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 4.15
• Publications: 10 publications found

Genes affected

IL2RG (HGNC:6010): (interleukin 2 receptor subunit gamma) The protein encoded by this gene is an important signaling component of many interleukin receptors, including those of interleukin -2, -4, -7 and -21, and is thus referred to as the common gamma chain. Mutations in this gene cause X-linked severe combined immunodeficiency (XSCID), as well as X-linked combined immunodeficiency (XCID), a less severe immunodeficiency disorder. [provided by RefSeq, Mar 2010]

IL2RG Gene-Disease associations (from GenCC):

• T-B+ severe combined immunodeficiency due to gamma chain deficiency

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Ambry Genetics, Myriad Women’s Health
• Omenn syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000285171 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 7 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000206.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL2RG	NM_000206.3	MANE Select	c.202G>A	p.Glu68Lys	missense	Exon 2 of 8	NP_000197.1
	IL2RG	NM_001438870.1		c.202G>A	p.Glu68Lys	missense	Exon 2 of 7	NP_001425799.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL2RG	ENST00000374202.7	TSL:1 MANE Select	c.202G>A	p.Glu68Lys	missense	Exon 2 of 8	ENSP00000363318.3
	ENSG00000285171	ENST00000646505.1		n.202G>A		non_coding_transcript_exon	Exon 2 of 12	ENSP00000496673.1
	IL2RG	ENST00000482750.6	TSL:5	c.202G>A	p.Glu68Lys	missense	Exon 2 of 7	ENSP00000421262.2

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 21

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
2	-	-	X-linked severe combined immunodeficiency (2)
1	-	-	Combined immunodeficiency, X-linked (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.1
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.79
Sift	Benign	0.14	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.55
MutPred		0.93		Gain of methylation at E68 (P = 0.0044)
MVP		1.0
MPC		1.4
ClinPred		0.94	D
GERP RS		5.4
PromoterAI		-0.011	Neutral
Varity_R		0.69
gMVP		0.97
Mutation Taster		=76/24	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1057520644; hg19: chrX-70330814;